Pantothenic acid is a commercially significant vitamin which is used in cosmetics, medicine, human nourishment and in animal nourishment.
Pantothenic acid can be produced by chemical synthesis or biotechnologically by the fermentation of suitable microorganisms in suitable nutrient solutions. DL-pantolactone is an important intermediate stage in the chemical synthesis. It is produced in a multi-stage process from formaldehyde, isobutylaldehyde and cyanide. In further method steps the racemic mixture is separated and D-pantolactone condensed with .beta.-alanine and D-pantothenic acid obtained. The advantage of the fermentative production with microorganisms resides in the direct formation of the desired stereoisomeric D-form, which is free of L-pantothenic acid.
Various types of bacteria such as, for example, Escherichia coli, Arthrobacter ureafaciens, Corynebacterium erythrogenes, Brevibacterium ammoniagenes and also yeasts such as, for example, Debaromyces castellii can produce D-pantothenic acid in a nutrient solution containing glucose, DL-pantoic acid and .beta.-alanine, as is shown in EP-A 0,493,060. EP-A 0,493,060 also shows that the formation of D-pantothenic acid is improved in the case of Escherichia coli by amplification of pantothenic-acid biosynthetic genes from E. coli, which are contained on the plasmids pFV3 and pFV5, in a nutrient solution containing glucose, DL-pantoic acid and .beta.-alanine.
EP-A 0,590,857 and U.S. Pat. No. 5,518,906 describe mutants derived from Escherichia coli strain IFO3547 such as FV5714, FV525, FV814, FV521, FV221, FV6051 and FV5069 which carry resistance genes against various antimetabolites such as salicylic acid, .alpha.-ketobutyric acid, .beta.-hydroxyaspartic acid, O-methylthreonine and .alpha.-ketoisovaleric acid and produce D-pantothenic acid in a nutrient solution containing glucose, pantoic acid and in a nutrient solution containing glucose and .beta.-alanine. E-A 0,590,857 and U.S. Pat. No. 5,518,906 also show that after the amplification of the pantothenic-acid biosynthesis genes contained on the plasmid pFV31, in the strains cited above, the production of D-pantoic acid is improved in a nutrient solution containing glucose and that the production of D-pantothenic acid is improved in a nutrient solution containing glucose and .beta.-alanine.
Moreover, WO97/10340 shows that the production of pantothenic acid can be further increased in strains of Escherichia coli forming pantothenic acid by elevating the activity of the enzyme acetohydroxy-acid synthase II, an enzyme of valine biosynthesis.